title: A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy.
abstract: BACKGROUND
  We performed the first multiple dose study of remimazolam designed to assess both the feasibility of maintaining suitable sedation during colonoscopy and reversing the sedative effects of remimazolam with flumazenil.
  
  
  METHODS
  Healthy volunteers received fentanyl followed by remimazolam for sedation during colonoscopy. Three dose groups of 15 volunteers each received remimazolam in increasing initial doses, plus top-up doses to maintain sedation for a 30-minute period. In a separate double-blind crossover part of the trial, 6 volunteers were sedated with a single high dose of remimazolam, followed by flumazenil or placebo to reverse the sedation.
  
  
  RESULTS
  Successful sedation that was adequate for colonoscopy was achieved in >70% of subjects. After the procedure, subjects rapidly recovered to fully alert, with a median of <10 minutes overall. Failures were due to the inability to sedate or adverse events, with 1 subject failing due to hypotension (arterial blood pressure 80/40) and low SpO2 (<90%). There were no serious adverse events reported, and no events that were unexpected with the combination of a benzodiazepine and fentanyl. The study also showed that sedation was rapidly reversible (1.0 minutes flumazenil vs 10.5 minutes placebo) without resedation.
  
  
  CONCLUSIONS
  Remimazolam has the attributes of a sedative drug, with success rates comparable with recent studies of other drugs. Remimazolam provided adequate sedation in 33 of 44 subjects undergoing colonoscopy, and its sedative effects were easily reversed with flumazenil.
authors.affiliation: From the *Division of Digestive Diseases and †Department of Anesthesiology, Johns Hopkins Hospital, and ‡Early Phase Clinical Unit, PAREXEL, Baltimore, Maryland; §Clinical Development, PAION UK Ltd, Cambridge, United Kingdom; and ‖Clinical Development, PAION Deutschland, GmbH, Aachen, Germany.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Worthington
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Antonik
authors.forename: D Ronald
authors.initials: DR
authors.lastname: Goldwater
authors.forename: James P
authors.initials: JP
authors.lastname: Lees
authors.forename: Karin
authors.initials: K
authors.lastname: Wilhelm-Ogunbiyi
authors.forename: Keith M
authors.initials: KM
authors.lastname: Borkett
authors.forename: Mack C
authors.initials: MC
authors.lastname: Mitchell
mesh_terms: D000931:Antidotes / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology*; D003113:Colonoscopy / Q000295:instrumentation / Q000379:methods*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male
chemical_list: D000931:Antidotes; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D005442:Flumazenil; C522201:remimazolam